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At least 1,063 records · Page 59Linked to original sources
PubMed1998

Selective outgrowth and differential tropism of amacrine and photoreceptor axons to cell targets during early development in vitro.

The axonal guidance and outgrowth in retinal neurons were investigated in cultures of pure retinal neurons (control) or in cocultures with heterologous BC3H-1 cells. Under control conditions, only about 10% of retinal neurons developed axons; coculturing with BC3H-1 cells induced early axonal outgrowth and guidance to BC3H-1 cells in most amacrine neurons. Both mechanisms were dependent on laminin and neural cell-adhesion molecules (N-CAMs) released by BC3H-1 cells, because they were prevented by antibodies directed against these molecules. The protein kinase C (PKC) inhibitor, staurosporine, reduced the effect of laminin on amacrine axonal outgrowth, suggesting that this effect was mediated by PKC. The occurrence of structures resembling synaptic boutons and the expression of synaptophysin at the amacrine axon ends of heterologous connections suggested that amacrine axons establish true synaptic contacts rather than simply overlapping with the BC3H-1 cells. In contrast to the heterologous contacts with BC3H-1 cells, the amacrine-amacrine axonal contacts observed in the cocultures were independent of laminin and N-CAM. Axonal outgrowth occurred in about 10% of the photoreceptors and was not affected by BC3H-1 cells or by substratum pretreatment with laminin or N-CAM. These results show that different mechanisms affect axonal outgrowth and guidance in amacrine and photoreceptor neurons in vitro, and they suggest that similar mechanisms could contribute to the development of the scaffold of axon pathways in the retina in vivo.

Animals↗
PubMed2004

Phosphodiesterase type 5 inhibitor differentiation based on selectivity, pharmacokinetic, and efficacy profiles.

The mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors (i.e., sildenafil, tadalafil, and vardenafil) involves inhibition of the PDE5 isoenzyme located in penile vascular smooth muscle cells. Sexual stimulation triggers the release of nitric oxide (NO), stimulating the release of guanylyl cyclase, leading to an increase in intracellular cyclic guanosine monophosphate (cGMP) concentrations, a decrease in intracellular calcium, and ultimately relaxation of the vascular smooth muscle in the corpus cavernosum and penile erection. The PDE5 inhibitors have no effect on the penis in the absence of sexual stimulation. Although the various PDE5 inhibitors differ with respect to selectivity and pharmacokinetic profiles, efficacy and safety of these agents are comparable in broad populations of men with erectile dysfunction (ED), including those with diabetes or those taking multiple antihypertensive agents. The most frequently reported adverse events of the PDE5 inhibitors are related to their mild vasodilatory effects and include headache, flushing, dyspepsia, and nasal congestion or rhinitis. Side effects are generally reversible and tend to diminish during continued treatment. Differences in pharmacokinetic properties among the PDE5 inhibitors include the fact that sildenafil and vardenafil have a shorter duration of action (approximately 4 h) compared with the longer period of responsiveness observed with tadalafil (up to 36 h). In addition, in the presence of high-fat food, absorption of sildenafil and vardenafil may be delayed; however, the rate and extent of tadalafil absorption are unaffected by high-fat food.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Differential expression of selected mitochondrial genes in hibernating little brown bats, Myotis lucifugus.

High rates of non-shivering thermogenesis by brown adipose tissue accompanied by additional shivering thermogenesis in skeletal muscle provide the powerful reheating of body organs that allows hibernating mammals to return from their state of cold torpor back to euthermic function. Previous studies have suggested that changes to brown adipose mitochondria occur during hibernation and are partially responsible for its capacity for non-shivering thermogenesis. The current study shows that selected mitochondrial enzyme activities are elevated and selected genes and proteins are induced during torpor in brown adipose tissue of the little brown bat, Myotis lucifugus. Cytochrome oxidase activity in brown adipose tissue was more than 3-fold higher during torpor than in euthermic animals. Transcript levels of mitochondria-encoded genes, coxII and nad4, were also 3-4-fold higher during torpor, as evidenced by northern blotting. By contrast, transcripts of these genes were unchanged in skeletal muscle during torpor. Protein levels of carnitine palmitoyl transferase-1beta, an enzyme embedded in the outer membrane of the mitochondria that is the rate-limiting step enzyme in beta-oxidation, were also elevated by 2-fold during torpor in brown adipose but were unchanged in skeletal muscle. Cloning and sequencing of a 624 bp segment of cpt-1beta revealed a number of amino acid substitutions in the bat protein as compared to CPT-1beta from other mammals; these may be beneficial for enzyme function at low body temperatures during torpor. This study provides further evidence for a key role of mitochondria in hibernation.

Adipose Tissue, Brown↗
PubMed1996

Selective hippocampal lesions differentially affect the phenotypic fate of transplanted neuronal precursor cells.

RN33B cells, a CNS-derived neuronal precursor cell line, transplanted into normal adult rat hippocampus can survive and morphologically differentiate with their ultimate morphology dependent on the integration site. This study examined the differentiation and structural integration of RN33B cells transplanted into the lesioned adult hippocampus. Pyramidal neurons of the CA1-3 regions or granular neurons in the dentate gyrus were preferentially destroyed by unilateral intraventricular kainic-acid or intradentate colchicine injections, respectively. One week after the lesion, a suspension of undifferentiated beta-galactosidase (beta-gal)-labeled RN33B cells was stereotaxically transplanted into the lesioned or the contralateral hippocampus. After 5-7 weeks, sections of the recipient brains were analyzed by toluidine blue staining and immunohistochemistry for beta-gal, GFAP, and OX-42. A reactive gliosis was observed on the lesioned side which persisted up to 7 weeks postlesion (the latest time point examined). RN33b cells survived in the lesioned hippocampus and assumed variable morphologies depending on the hippocampal layer into which they integrated. Only RN33B cells located in intact or partially damaged cell layers or in the unlesioned contralateral hippocampus differentiated with morphologies similar to those of endogenous neurons characteristic of those layers. Cells located in layers completely depleted of endogenous neurons assumed bipolar morphologies or sent out multiple processes with no structural polarity, unlike the neuronal morphologies characteristically seen in intact hippocampal cell layers. These data suggest that the presence of some endogenous neurons and partially conserved cytoarchitectural organization are essential for immortalized neuroepithelial precursor cells to differentiate into region-specific neuronal cell types.

Animals↗
PubMed2000

Expression of neurexin Ialpha splice variants in sympathetic neurons: selective changes during differentiation and in response to neurotrophins.

Neurexins are a surprisingly diverse group of alternatively spliced proteins possibly involved in neural cell recognition processes. We find neurexin Ialpha and its splice variants highly conserved between mammals and birds. In vivo, neurexin Ialpha is expressed in sympathetic neurons during target innervation and relative expression levels of splice variants change with development. In vitro, no such changes are observed in the absence of growth factors, indicating that interactions with the environment are required to modify the splicing pattern. Specific alterations in splice variant expression are induced in vitro by neurotrophins. Expression patterns of splice variants in vivo and neurotrophin-induced regulation without changes in cell composition in vitro demonstrate that neurexin splice variant expression varies during differentiation of individual neurons. Our data suggest that changes in neurexin splice variants contribute to alterations of neuronal cell surface properties during target innervation.

Alternative Splicing↗
PubMed1996

Differential inhibition by selective phosphodiesterase inhibitors of antigen, LTC4 and histamine-induced contraction of guinea-pig isolated trachea.

Antigen (ovalbumin)-induced contraction of guinea-pig isolated trachea, which largely resulted from the endogenous release of peptidoleukotrienes, was strongly inhibited by the non-selective phosphodiesterase (PDE) inhibitor theophylline and, more potently, by the selective PDE type IV inhibitors rolipram and Ro 20-1724. It was also strongly inhibited by the PDE type V inhibitor zaprinast, but much less so by the PDE type III inhibitor siguazodan and milrinone. Similar results were obtained in trachea minus epithelium. In contrast to their effects vs. allergic airway smooth muscle contraction, both milrinone and siguazodan potently relaxed leukotriene C4 (LTC4)-induced contraction in isolated trachea from non-sensitized animals. In this assay, rolipram, Ro 20-1724 and zaprinast were less active compared to their effects vs. ovalbumin-induced contraction, whereas theophylline had equivalent potency in the two tests. The relative potencies of rolipram and siguazodan in relaxation of trachea were similar when added prior to or after either LTC4 or histamine. These results suggest that the higher potency of selective PDE type IV & V inhibitors compared with PDE type III inhibitors vs. ovalbumin-induced contraction is due to their greater inhibition of anaphylactic mediator release. The converse is true if we consider their bronchodilator actions, although the superior efficacy of selective PDE type III inhibitors over PDE type IV inhibitors may vary in sensitized vs. non-sensitized animals. The present results are in agreement with a previous study showing that low concentrations of a beta 2-agonist increased the relaxant effect of selective PDE type IV inhibitors in guinea-pig trachea. The present data indicate that prophylactic use of selective PDE type IV inhibitors combined with therapeutic use of low dose inhaled beta-agonist might represent an alternative to the use of antiallergic or steroid therapy in asthma.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1986

A monoclonal antibody with binding and inhibiting activity towards human pancreatic carcinoma cells. I. Immunohistological and immunochemical characterization of a murine monoclonal antibody selecting for well differentiated adenocarcinomas of the pancreas.

The murine monoclonal antibody (MAb) BW 494 was characterized in relation to its tissue specificity, the epitope recognized, in vitro and in vivo radiolocalization and its potential to mediate antibody dependent cellular cytotoxicity (ADCC) and complement mediated cytolysis (CMC). The MAb defined carbohydrate epitope located on a greater than 200 k daltons glycoprotein was mainly expressed on the majority of well differentiated adenocarcinomas of the pancreas. Furthermore, the epitope is accessible to MAb BW 494 in vivo, allowing an enrichment of radioactive antibody at the tumor site in nude mice. Additionally, MAb BW 494 is able to use human peripheral blood lymphocytes as effector cells for ADCC reactions against appropriate tumor target cells in vitro. In contrast, the antibody does not mediate human or rabbit CMC.

Adenocarcinoma↗
PubMed1980

Avoidance behavior in rats selectively bred for differential alcohol sensitivity.

"Most affected" (MA) and "least affected" (LA) rats, bred for extremes in motor impairment following an alcohol challenge, differed in their performance on two active avoidance tasks. In two-way shuttle avoidance, the MA line performed significantly better than the LA group, both in terms of response latencies and percent avoidances. The inferior performance of the LA line persisted across the 15 days of testing, and appeared to reflect an difference in asymptotic performance levels. In one-way avoidance, the MA line showed significantly better acquisition than the LA group; however, this difference dissipated across the 3 days of training. When tested following alcohol administration in either the one- or two-way avoidance paradigm, the MA rats showed a greater performance deficit than LA animals. These data were interpreted as indicating the generality of alcohol-related line differences to a situation motivated by aversive consequences. Moreover, the line difference in avoidance acquisition represents one of the few non-drug-related phenotypic differences that have been found in these lines. In previous generations, disparate base rates of wheel running have been reported, and the data presented here confirm and extend this finding.

Animals↗
PubMed1982

Differential effects of selective alpha 1- and alpha 2-adrenoceptor agonists on intraocular pressure in the conscious rabbit.

In the present study the influence of topically applied selective alpha 1- and alpha 2-adrenoceptor agonists on intraocular pressure and the diameter of the pupil was investigated in conscious rabbits. Selective stimulation of the alpha 1-subtype of receptors induced an elevation in intraocular pressure, accompanied by mydriasis, whereas stimulation of the alpha 2-subtype caused a marked and dose-dependent ocular hypotensive response, which could be blocked by the selective alpha 2-adrenoceptor antagonist yohimbine. After application of the non-selective alpha-adrenoceptor agonist clonidine the alpha 2-adrenoceptor mediated decrease in IOP is probably counteracted by a pressor effect due to the stimulation of alpha 1-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1990

Differential ability of selective and non-selective dopamine agonists to induce climbing in the rat indicates the involvement of both D-1 and D-2 receptors in this behaviour.

Approximately 50% of female Wistar rats examined exhibited a continuous climbing response to a screening dose of apomorphine. In animals identified as climbing, the mixed D-1/D-2 agonists apomorphine, pergolide and L-dopa, and the indirectly acting agonists nomifensine and (+)-amphetamine, induced a dose-related climbing response. The selective D-1 agonist SKF 38393 caused only minimal climbing, and the selective D-2 agonists bromocriptine, lisuride and LY 141865 induced a weak climbing response. All agonists examined, except SKF 38393, caused a dose-related stereotypy response. The selective D-1 antagonist SCH 23390, and the selective D-2 antagonist sulpiride, both produced maximum inhibition of apomorphine-induced climbing. SCH 23390 also inhibited stereotyped behaviour, but sulpiride was less effective. In animals identified as "non-climbers" using the screening dose of apomorphine, only L-dopa induced a marked climbing response. Nomifensine and bromocriptine produced weak or discontinuous climbing in this group, while the other agonists examined had little or no effect. In contrast all drugs examined, except SKF 38393, induced stereotyped behaviour of the same intensity observed in the "climbers". It is concluded that stimulation of both D-1 and D-2 receptors is necessary to induce a continuous climbing behaviour in rats. D-2, but not D-1 stimulation, alone can induce a weak or discontinuous climbing response, but concomitant stimulation of D-1 receptors potentiates this effect. Failure of some rats to climb does not appear to be related to relative degrees of D-1 and D-2 stimulation.

Amphetamine↗
PubMed1985

Differential effects of selective and non-selective neuroleptics on intracellular and extracellular cyclic AMP accumulation in rat striatal slices.

Cyclic AMP was measured in both striatal slices and in the incubation medium after exposure to dopamine and dopamine antagonist. Dopamine increased cyclic AMP in both tissue and medium. The effect of dopamine was enhanced by sulpiride and domperidone, and to a lesser extent by haloperidol, but alpha-fluphenthixol had only an inhibitory effect. The enhancement by sulpiride was stereoselective and totally suppressed by the D1 antagonist SCH 23390. Cyclic AMP in the medium provided the more sensitive measure of drug effect and increased linearly for up to 20 min., whereas the nucleotide in tissue remained stable or declined after 10 min. It is concluded that: the increase in dopamine-stimulated cyclic AMP efflux caused by D2 antagonists reflects increased intracellular cyclic AMP accumulation rather than an effect on the efflux mechanism; dopamine enhances cyclic AMP accumulation via a D1 receptor, and simultaneously inhibits it through a D2 receptor; and changes in D1 receptor-stimulated cyclic AMP formation in striatum may not be related to the clinical actions of neuroleptics. It remains possible that D2 receptor-mediated inhibition of cyclic AMP accumulation stimulated by a different agonist system may underlie some of the therapeutic actions of dopamine agonists and antagonists.

Animals↗
PubMed1994

Differential effects of selective tachykinin NK2 receptor antagonists in rat spinal cord.

The effects of intrathecally (i.t.) injected selective tachykinin NK2 receptor antagonists, MEN 10,207, MEN 10,376 and R396, on the spinal effect of neurokinin A were studied in decerebrate, spinalized, unanesthetized rats. I.t. neurokinin A (7 pmol) briefly facilitated the flexor reflex, an effect that was dose dependently inhibited by pretreatment with MEN 10,207 and MEN 10,376 with similar and high potency. I.t. R396 itself caused strong facilitation of the flexor reflect. At lower doses, the effect of i.t. neurokinin A was potentiated by R396. R396 only exhibited moderate antagonism of neurokinin A-induced reflex facilitation even at very high doses. It has been proposed that the tachykinin NK2 receptor may be further classified into two subtypes, NK2A and NK2B, with MEN 10,207 and MEN 10,376 having high affinity for the former and R396 for the latter. Our results suggested that the tachykinin NK2 receptor in rat spinal cord which mediates the excitatory effect of neurokinin A may belong to the NK2A subpopulation of receptors.

Amino Acid Sequence↗
PubMed1982

Selective decline in differentiating capacity of immunohemopoietic stem cells with aging.

Bone marrow (BM) from young (3 months) and old (24 months) C57BL/6J mice were tested for the total number of colony forming units, which remain unchanged with age. The BM from both groups was used to reconstitute syngeneic, lethally irradiated mice that were 3 months' old. The reconstituted mice were followed for a period of 12 months for their ability to generate cell-mediated responses in mixed lymphocytic cultures and cultures containing the T mitogens--concanavalin A and phytohemagglutinin. For the first 8 months, mice given BM from young or old mice responded to a similar degree. Later, cellular immune responses of the mice reconstituted with BM from old mice declined markedly compared to those reconstituted with BM from young mice, although there was no detectable difference between the two groups in the hematopoietic compartment.

Aging↗
PubMed1987

1,25-Dihydroxyvitamin D3 and phorbol esters (TPA) may induce select in vitro differentiation pathways in the HL60 promyelocytic cell line.

Monocytic features can be induced in the myeloid cell line HL60 in order to provide a suitable in vitro model for the investigation of in vitro activity in mononuclear phagocytes. 1,25-Dihydroxyvitamin D3 (calcitriol) induced the HL60 cell line to express the monocytic differentiation antigen Leu M3 in about 30-50% of the cells along with an increase (up to 20%) in the expression of HLA-DR but not HLA-DQ class II antigen. Functional investigation showed that calcitriol-treated cells formed rosettes with sheep erythrocytes coated with an anti-sheep erythrocyte-specific IgG2a mouse MoAb and readily ingested them. In addition, these same sensitized erythrocytes were lysed in an 18-hr antibody-dependent cellular cytotoxicity (ADCC) assay. All together these data indicate the presence of functionally active Fc-IgG receptors (FcR). Sorting experiments demonstrated that only Leu M3+ HLA-DR+ cells contained the effector cell population; such was also the case for blood monocytes. This phenotypic profile was, however, not predictive per se of FcR presence and function, as 12,O-tetradecanoylphorbol-13-acetate (TPA)-induced HL60 cells neither formed rosettes nor phagocytosed nor exhibited ADCC activity, although they express Leu M3 and HLA-DR (as well as HLA-DQ) antigens. These results suggest that calcitriol and TPA cause the differentiation of HL60 cells along distinct pathways. On the other hand, different subpopulations with given predetermined differentiation capabilities may coexist in HL60 cell line. This hypothesis gains support by the observation that when TPA and calcitriol were added together to the undifferentiated cells, the resulting phenotypic pattern was representative of the different activities of both of the inducers as they were used separately.

Antigens, Neoplasm↗
PubMed1983

Differential effects of selective dopamine, norepinephrine or catecholamine depletion on activity and learning in the developing rat.

The present experiment investigated the behavioral changes which occurred following neonatal depletion of central catecholamine systems in the rat. The behavioral effects which resulted from selective dopamine (DA) depletion were compared with those resulting from selective norepinephrine (NE) depletion as well as depletion of both catecholamines (CA). Neonatal 6-hydroxydopamine (6-OHDA) was administered intracisternally at 5 days of age following pretreatment with desmethylimipramine in order to selectively deplete DA. NE levels were reduced by intraperitoneal injections of 6-OHDA at 1 and 2 days of age. Depletion of both catecholamines was effected by combining the procedures used for selective depletion of both DA and NE. Activity was time sampled during an hour at 3 preweanling ages. Avoidance and escape learning were measured in a T maze when pups were 20 days of age and in a Shuttlebox apparatus on day 28. Results revealed that DA and CA depleted animals were hyperactive in comparison to controls and displayed severe learning impairments in both T maze and Shuttlebox performance. In contrast, NE depleted animals showed activity levels which were similar to controls but were significantly impaired on both learning paradigms. These results suggest that selective lesions of DA and NE in infancy lead to a constellation of behaviors which are distinctly unique. The implications of these findings is discussed in terms of clinical research into the Attentional Deficit Disorder of childhood.

Animals↗
PubMed1985

Differential effects of selected dopaminergic agents on locomotor activity in normotensive and spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) exhibit a significantly higher level of spontaneous locomotor activity than age-matched normotensive controls (WKY). The direct-acting dopamine agonists, apomorphine and pergolide, produced a biphasic effect on locomotor activity levels in normotensive controls. Low doses of these agonists decreased activity levels, while higher doses of these agonists dramatically stimulated activity. In marked contrast to these results was the effect observed in the SHR, in which these agonists at all doses tested decreased activity. Amphetamine, a dopamine releaser, stimulated activity levels in both the WKY and SHR; however, the magnitude of the increase was somewhat attenuated in the SHR.

Amphetamine↗
PubMed1993

Differential effects of selective neurokinin agonists on phasic and tonic activity in rat ileal longitudinal muscle.

To test the hypothesis that different neurokinin receptors might be involved in the generation of either phasic or tonic muscular activity, selective ligands for the 6 neurokinin-1-receptor, [Sar9, Met(O2)]-SP, the neurokinin-2-receptor, [Nle10]-NKA4-10, and the neurokinin-3 receptor, [beta Asp4,MePhe7]-NKB4-10, were used to evaluate the excitatory effects of these agonists in the longitudinal rat ileal muscle in vitro. The excitatory effect was analyzed as total response (area under the curve) and as tonic or phasic (area under or within the peaks) activity. Substance P (SP, relative amount of phasic activity in comparison to total activity: 3 x 10(-8) M 87%, 3 x 10(-6) M 30%) and the neurokinin-2-receptor selective agonist [Nle10]-NKA4-10 (N-NKA: 3 x 10(-8) M 67%, 3 x 10(-6) M 59%) caused both tonic and phasic responses, with the percentage of phasic responses decreasing at higher concentrations. The neurokinin-1-receptor selective agonist [beta Ala4, Sar9, Met(O2)]-SP4-11 caused a predominantly tonic response with only a small phasic component (10(-8) M 27.1% 10(-6) M 13.8%). The selective neurokinin-3 receptor agonist [beta Asp4, MePhe7]-NKB4-10 caused a predominantly phasic motor response (SM-SP: 3 x 10(-8) M 98%, 3 x 10(-6) M 87%). Tetrodotoxin (TTX 10(-6) M), omega-conotoxin (CTX 10(-7) M) and atropine (10(-6) M) had no significant influence on the contractile responses to all four peptides, indicating a direct action on the smooth muscle cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗